Reduced bone formation in males and increased bone resorption in females drive bone loss in hemophilia A mice

• Type of Material: Article
• Authors: M. Neale Weitzmann, Emory University; Susanne Roser-Page, Atlanta VA Medical Center; Tatyana Vikulina, Emory University; Daiana Weiss, Emory University; Li Hao, Emory University; W. Hunter Baldwin, Emory University; Kanglun Yu, Augusta University; Natalia del Mazo Arbona, Augusta University; Meghan E. McGee-Lawrence, Medical College of Georgia; Shannon Meeks, Emory University; Christine Kempton, Emory University
• Language: English
• Date: 2019-02-12
• Publisher: American Society of Hematology: Blood Advances
• Publication Version: Final Published Version
• Copyright Statement: © 2019 by American Society of Hematology
• Final Published Version (URL): http://dx.doi.org/10.1182/bloodadvances.2018027557
• Title of Journal or Parent Work: Blood Advances
• ISSN: 2473-9529
• Volume: 3
• Issue: 3
• Start Page: 288
• End Page: 300
• Grant/Funding Information: M.E.M.-L. was supported by the National Institute on Aging, National Institutes of Health (grant AG036675).; M.N.W. was supported in part by the Biomedical Laboratory Research & Development Service of the VA Office of Research and Development (grant 5I01BX000105) and by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health (grants AR068157 and AR070091).
• Keywords: hemophilia A; bone fracture; F8TKO; male; bone volume; female
• Research Categories: Health Sciences, Medicine and Surgery

Abstract

Hemophilia A (HA), a rare X-linked recessive genetic disorder caused by insufficient blood clotting factor VIII, leaves affected individuals susceptible to spontaneous and traumatic hemorrhage. Although males generally exhibit severe symptoms, due to variable X inactivation, females can also be severely impacted. Osteoporosis is a disease of the skeleton predisposing patients to fragility fracture, a cause of significant morbidity and mortality and a common comorbidity in HA. Because the causes of osteoporosis in HA are unclear and in humans confounded by other traditional risk factors for bone loss, in this study, we phenotyped the skeletons of F8 total knockout (F8TKO) mice, an animal model of severe HA. We found that trabecular bone accretion in the axial and appendicular skeletons of male F8TKO mice lagged significantly between 2 and 6 months of age, with more modest cortical bone decline. By contrast, in female mice, diminished bone accretion was mostly limited to the cortical compartment. Interestingly, bone loss was associated with a decline in bone formation in male mice but increased bone resorption in female mice, a possible result of sex steroid insufficiency. In conclusion, our studies reveal a sexual dimorphism in the mechanism driving bone loss in male and female F8TKO mice, preventing attainment of peak bone mass and strength. If validated in humans, therapies aimed at promoting bone formation in males but suppressing bone resorption in females may be indicated to facilitate attainment of peak mass in children with HA to reduce the risk for fracture later in life.